The authors tested predictions, derived from a self-regulation model, about variables moderating the relationship between level of substance use (tobacco, alcohol, and marijuana) and problems associated with use. Data were from two independent studies of adolescents, with mean ages of 15.4 and 15.5 years (Ns = 1,699 and 1,225). Factor analysis indicated correlated dimensions of control problems and conduct problems. Protective moderation was found for variables indexing good self-control; risk-enhancing moderation was found for variables indexing poor self-control. These effects were generally independent of deviance-prone attitudes and externalizing symptomatology. Multiple-group structural modeling indicated moderation occurred for paths from life stress and coping motives and for paths from level to control and conduct problems. Moderation effects were also found for parental variables, peer variables, and academic competence.